Most recently, glutathione has come under increasing attention as a therapeutic agent. Glutathione has been suggested for the treatment of chemical toxicities, especially the toxicities associated with heavy metal poisoning and cancer chemotherapeutic regimes. See BE no. 904717 and ZA no. 8707502J. See also L. Domingo, et al., Toxicology vol. 62 pp. 203-211, 1990; Di Re, et al., Cancer Chemotherapy and Pharmacology, vol. 25, pp. 355-360, 1990; L. Cozzaglio et al., Tumori, vol. 76 pp. 590-594; M. T. Nobile et al., Tumori, vol. 75 pp. 257-258, 1989. Glutathione, in its reduced form, is known to be critical for optimal immune system function. Furukawa et al., Mechanisms of Aging and Development, vol. 38 pp. 107-117, 1987; Droge et al., Immunobiology, vol. 172 pp. 151-156, 1986; Suthanthiran, et al., Proceedings of the National Academy of Sciences, vol. 87 pp. 3343-3347, 1990.
Glutathione may be administered by a number of conventional techniques such as interperitoneally, by aerosol to the lungs, or intravenously. However, aerosol administration ha been shown not to raise the effective levels of glutathione in plasma. The other forms of administration mentioned above are painful, inconvenient, and not necessarily effective in providing long term, meaningful levels of glutathione in plasma. See Aebi et al., European Journal of Clinical Investigation, vol. 21, pp. 103-110, 1991.
Not surprisingly, oral dosage forms are preferable. One type of oral dosage form is the oral solution or suspension of glutathione. Oral solutions of reduced glutathione can be effectively delivered and absorbed in human subjects. Elevated plasma levels of glutathione can be realized through this form of administration. See Jones et al., FASEB Journal, vol. 3, p. A1250, 1990; "Glutathione Centennial: Molecular Perspectives and Clinical Implications", Academic Press, New York 1990, pp. 423-431.
While this represents a significant advantage over other forms of administration, oral suspensions of glutathione have disadvantages which render them much less desirable than solid oral dosage forms. Glutathione slurries have a foul, sulfurous taste which is thoroughly objectionable to a patient and difficult to mask. Furthermore, oral suspensions require fresh preparation because glutathione is unstable in aqueous solutions. This renders them inconvenient, and undesirable, particularly where long term compliance to a medical regimen by a patient is essential.
The desirability of solid dosage forms such as a tablets or capsules is therefore manifest. Unfortunately, glutathione is not very accommodating to such dosage forms.
Reduced L-glutathione has an unusually high electrostatic charge. As described in more detail herein, this renders the material difficult to encapsulate or tablet. This problem is greatly exacerbated during processing. For example, standard encapsulation equipment moves powder from a reservoir hopper into a dosing trough, then into a dosator funnel. From the dosator funnel, the powder material is emptied into empty capsules or tablet dies which are then sealed or pressed and cleaned in a cleaning/polishing machine. Thereafter, the filled cleaned capsules or tablets are moved to any of a number of different packaging devices. But much like a balloon rubbed against a sweater, glutathione picks up significant additional electrostatic charge during this processing. The glutathione material then sticks and accumulates to the processing machinery, wreaking havoc with its smooth and consistent operation.
Moreover, it is almost impossible to obtain complete and reliable fill weights in capsules or tablets. Overfilling and underfilling are common. Most frustratingly, however, is the problem of highly variable fill levels between batches and in fact, between individual capsules in a batch.
The problems with the processing of glutathione do not end there.
Once the capsules or tablets have been completed, they are cleaned and polished. This process often involves brushing, wiping and the like to remove residual powder from the exterior of the capsule. The movement of the capsules is rapid, with rotating brushes, or cloths buffing them. This combination adds an additional charge to the interior powder, as well as powder clinging to the inner and outer surfaces of capsules. Because of the high electrostatic forces generated during the prior processing steps, glutathione remains on the surface of the tablet or capsule. Moreover, the very process of attempting to remove excess glutathione from the exterior surface of the capsule merely increases the amount of electrostatic charge which results. The net of all the acquired and inherent charges becomes so great at this stage that visible sparking, three to four centimeters long, is routinely experienced when attempting to handle glutathione capsules or tablets having a fill weight of 250 mg of glutathione or more.
Other problems are exhibited when attempting to package high fill weight glutathione capsules and tablets. For example, when a vibrating hopper with inclined guide device is used to transport the now cleaned capsules to individual packages, the highly charged glutathione capsules or tablets tend to fall onto the incline guide and stick thereto. Even when vibration is applied to the inclined guide, to urge the solid dosage form onward, packages tend to be underfilled or overfilled more often than they are filled to the appropriate level.
Other types of packaging devices utilize oscillating gravity feeders. These feed devices lift the capsules or tablets up into small enclosed guide tracks that depend on gravity. However, this process adds additional charge and the highly charged capsules or tablets entering the opening of the guide tracks frequently would stop within the enclosed guides and jam.
To overcome these problems, a number of solutions have been suggested. First, it is possible to use relatively low amounts of glutathione. This will limit the amount and the effect of the electrostatic buildup. Unfortunately, experts believe that relatively high daily dosages of glutathione will be required to be effective in the treatment of the toxicities of adriamycin, cisplatin and cyclophosphamide toxicities, cardiovascular disorders and, immunologic disorders such as acquired immune deficiency syndrome ("AIDS"). To attain such daily dosage levels with low fill weight glutathione solid dosage forms, literally dozens of capsules would have to be consumed on a daily basis. Long term compliance by a patient to such an unwieldy dosage regimen is difficult. This is particularly true in the case of persons who find it difficult to take tablets or capsules in the first place.
It is also possible to mix small amounts of glutathione, below 100 mg with, for example, an overwhelming amount of lubricants, excipients, fillers, binders or other adjuvants. Again, however, accommodating high daily dosages will require the daily administration of possibly dozens of tablets or capsules a day. In addition, to accommodate the various adjuvants, the size of the tablet or capsule may need to be increased, making it more difficult for patients to swallow and exacerbating the problems encountered with administration to people who are idiosyncratic about swallowing tablets or capsules. In addition, the prolonged ingestion of excipient or additive rich capsules or tablets in the quantities necessary to administer sufficient glutathione on a daily basis is less than desirable. Adverse reactions to excipients and additives include: 1) serious gastrointestinal reactions, such as nausea, vomiting, cramps, bloating, diarrhea and persistent flatulence; 2) skin rashes; 3) dizziness, tinnitus; 4) hypotension.
Such an administration scheme represents almost the worst of all possible worlds.
The present inventors attempted a number of possible solutions with regard to high glutathione level capsules and tablets. First, the present inventors attempted the use of small and large amounts of magnesium stearate, calcium carbonate, talc, silicon dioxide, starches and/or dry powdered ascorbic acid. Rather than dissipating the electrostatic charge, some of these agents actually increased the problem. The inventors also attempted to generate a flow of ions, positively and negatively charged, directed at the capsules and the powder. These techniques did not, however, prove satisfactory in the reliable production of large numbers of high fill weight glutathione capsules or tablets.
The problems associated with the production of glutathione tablets are further complicated by the relatively low bulk density and poor compressibility of reduced L-glutathione.
The present inventors have, however, discovered a solution to the problems associated with the production of high glutathione content capsules and tablets.